Mechanisms and models of peripheral CD4 T cell self-tolerance

Abstract

Each response made by our immune system is either to promote or to prevent immune reactivity. That the immune system can successfully achieve both goals under specific biological conditions depends on central and peripheral tolerance mechanisms. Over the years, various experimental systems have been generated to study peripheral CD4 T cell tolerance. The experimental approaches are clearly diverse, but can be broadly categorized into those involving, tolerogenic, antigen injections, the use of transgenic mice (antigen transgenics, TCR transgenics and the combination thereof) and transplantation models. Results of these studies suggested a number of potential mechanisms mediating peripheral CD4 T cell tolerance, including clonal deletion, anergy and immune regulation. While the available systems all presented with their own limitations, they nevertheless provided a foundation from which our understanding of peripheral CD4 T cell tolerance will be built. In addition, previous studies done to examine CD8 T cell tolerance left with us some potentially helpful clues and ideas about how CD4 T cell tolerance should be studied. However, our current understanding on the immunity/tolerance decision made by CD4 T cells in the periphery remains incomplete. Evidence accumulated thus far favors the view that peripheral tolerance, unlike central tolerance, may not primarily determine the selection of specificities within the baseline T cell repertoire but may instead regulate cellular responses within the repertoire, in terms of both expansion/contraction and differentiation. Nevertheless, more robust and refined models need to be developed before we can make definitive conclusions about the potential role of peripheral tolerance in repertoire selection mediated by deletion of self-reactive cells.

The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

“…More detailed studies will be required to determine the precise contribution of tissue 'health' or homeostasis [2,3,40,41] in any tolerance generated with pre-immunocompetence transplants. Interestingly, we found greater acceptance of MHC mismatched compared to multiple minor-H mismatched pre-immunocompetence islet transplants; a result that is consistent with an increased importance for the indirect pathway in triggering the anti-donor response to long-healed transplants, where a paucity of donor antigen-presenting cells is expected [42-44]. Without donor APCs the direct response is expected to be greatly reduced, leaving T cells triggered via the indirect pathway, that are only able to engage and attack cells of the donor transplant if they are MHC matched.…”

Time, Space and Contextual Models of the Immunity Tolerance Decision: Bridging the Geographical Divide of Zinkernagel and Hengartner's ‘Credo 2004’

“…As we have discussed previously, peripheral tolerance to tissue-specific antigens is a theoretical necessity [7,8]. While central tolerance may eliminate the vast majority of high-affinity antiself T and B cells, there is substantial indirect evidence for a limited number of antigens being present in the periphery and not centrally.…”

“…However, in development-context, amplification of the positive response by costimulation is, under most conditions, necessary to generate a complete response that is fully effective at eliminating the target antigen. We have argued previously that Cohn's T-cell help is more appropriately considered the key controller of class and memory in an immune response rather than the determinant of a selfnonself discrimination [7,8]. While the presence of T-cell help, or simply an increased precursor frequency of collaborating responding cells, can help prevent tolerance, this does not mean that tolerance is normally established to self-antigens because of the lack of T-cell help.…”

The Molecular Mechanisms of Regulatory T cell Immunosuppression

“…Tolerance is achieved in part by selecting against self-reactive T lymphocytes during ontogeny in the thymus, a powerful mechanism termed as central tolerance (Gershon and Kondo, 1971;Bonomo et al, 1995;Zheng et al, 2003;Kyewski and Klein, 2006;St Clair et al, 2007). However, there are "peripheral" tolerance mechanisms that divert immune responses away from self and toward appropriate pathogens (Miller and Morahan, 1992;Arnold et al, 1993;Anderson and Chan, 2004;Anderson et al, 2005;St Clair et al, 2007;Moraes-Vasconcelos et al, 2008).…”

“…Peripheral deletion pathways are typically clonal in that specific engagement of antigen receptors in the T-cells activity on internal death program leading to deletion (Lenardo, 1991;Hornung, 1997). Other mechanisms of peripheral tolerance not discussed in this review include rendering selfspecific cells inactive (anergy), deviating the immune system to innocuous or protective responses (immune deviation), adjusting lymphocyte responses so that available antigen levels are below the threshold of detection (clonal ignorance) or suppression of local responses by biological mediators such as CTLA-4, IL-10, and TGF-β (suppression or regulation; Schwartz, 2003;Anderson and Chan, 2004).…”